Drugs are most conventionally administered either orally or by injection. Unfortunately, many medicaments are completely ineffective or of radically reduced efficacy when orally administered since they either are not absorbed or are adversely affected before entering the blood stream and thus do not possess the desired activity. On the other hand, the direct injection of the medicament into the blood stream, while assuring no modification of the medicament in administration, is a difficult, inconvenient and uncomfortable procedure, sometimes resulting in poor patient compliance. Transdermal drug delivery offers improvements in these areas. However, in many instances, the rate of delivery or flux of many agents via the passive transdermal flux is too limited to be therapeutically effective.
One method of increasing the transdermal flux of agents relies on the application of an electric current across the body surface referred to as “electrotransport.” “Electrotransport” refers generally to the passage of a beneficial agent, e.g., a drug or drug precursor, through a body surface, such as skin, mucous membranes, nails, and the like where the agent is induced or enhanced by the application of an electrical potential. The electrotransport of agents through a body surface may be attained in various manners. One widely used electrotransport process, iontophoresis, involves the electrically induced transport of charged ions. Electroosmosis, another type of electrotransport process, involves the movement of a solvent with the agent through a membrane under the influence of an electric field. Electroporation, still another type of electrotransport, involves the passage of an agent through pores formed by applying a high voltage electrical pulse(s) to a membrane. In many instances, more than one of these processes may be occurring simultaneously to a different extent. Accordingly, the term “electrotransport” is given herein its broadest possible interpretation, to include the electrically induced or enhanced transport of at least one charged or uncharged agent, or mixtures thereof, regardless of the specific mechanism or mechanisms by which the agent is actually being transported. Electrotransport delivery generally increases agent flux during transdermal delivery.
Another method of increasing the agent flux involves pre-treating the skin with, or co-delivering with the beneficial agent, a skin permeation enhancer. A permeation enhancer substance, when applied to a body surface through which the agent is delivered, enhances its flux therethrough such as by increasing the permselectivity and/or permeability of the body surface, creating hydrophilic pathways through the body surface, and/or reducing the degradation of the agent during transport. This methodology is typically used when the drug is delivered transdermally by passive diffusion.
There also have been many attempts to mechanically penetrate or disrupt the skin thereby creating pathways into the skin in order to enhance the transdermal flux. Some of the earliest attempts to enhance transdermal drug flux involved abrading the skin (e.g., with sandpaper) or tape-stripping the skin to disrupt the stratum corneum. More recently, there have been attempts to pierce or cut through the stratum corneum with tiny piercing/cutting elements. See for example, U.S. Pat. Nos. 5,879,326 issued to Godshall, et al., 3,814,097 issued to Ganderton, et al., 5,279,544 issued to Gross, et al., 5,250,023 issued to Lee, et al., 3,964,482 issued to Gerstel, et al., Reissue 25,637 issued to Kravitz, et al., and PCT Publication Nos. WO 96/37155, WO 96/37256, WO 96/17648, WO 97/03718, WO 98/11937, WO 98/00193, WO 97/48440, WO 97/48441, WO 97/48442, WO 98/00193, WO 99/64580, WO 98/28037, WO 98/29298 and WO 98/29365. These devices use piercing elements of various shapes and sizes to pierce the outermost layer (i.e., the stratum corneum) of the skin. The piercing elements disclosed in these references generally extend perpendicularly from a thin, flat member, such as a pad or sheet. The piercing elements or microprotrusion in some of these devices are extremely small, some having dimensions (i.e., length and width) of only about 25-400 μm and a microprotrusion thickness of only about 5-50 μm. These tiny piercing/cutting elements make correspondingly small microslits/microcuts in the stratum corneum for enhanced transdermal agent delivery therethrough.
It has now been discovered that in the case of human skin, the pathways created by the microslits/microcuts are quickly closed and sealed by the skin's natural healing processes. Although this process is not completely understood at this time, it is believed that it is closely related to wound healing. Wound healing is a complex phenomenon involving many biological processes. The earliest event, taking place within minutes, in the wound healing process is the formation of a fibrin clot. In addition, many pro-inflammation mediators are liberated or generated during the early phase of wound healing. Liberation of these factors triggers keratinocyte migration, leukocyte infiltration, fibroblast proliferation which result in protein degradation, protein synthesis and tissue remodeling. In the end, reformation of the skin barrier is achieved. In some instances, the enhancement in transdermal agent flux provided by these pathways is completely eliminated within several hours of making the pathways. Thus, there is a need for a method which can prevent, or at least delay the skin's natural healing processes in order to allow transdermal flux of agents, through microcuts/microslits over longer periods of time (e.g., longer than about one hour) when the delivery methodology utilizes micropiercing elements.
The present invention fulfills this and related needs.